1. Field of the Invention
The present invention relates to a crystalline form of the sodium salt of pravastatin, which is known by the chemical name 1-naphthaleneheptanoic acid, 1,2, 6,7,8,8a-hexahydro-xcex2, xcex4,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, mono sodium salt, which is useful as a pharmaceutical substance. The present invention further relates to the method for its preparation and isolation, to a pharmaceutical formulation containing the sodium salt of pravastatin in the crystalline form and a pharmaceutically acceptable carrier, and to the pharmaceutical method of treatment.
2. Description of the Related Art
Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, fluvastatin and cervastatin and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, some are obtained by treating the fermentation products using the methods of chemical synthesis (simvastatin) or they are the products of total chemical synthesis (fluvastatin, atorvastatin and cervastatin).
Processes for the preparation of the sodium salt of pravastatin in a solid form known from the prior art comprise, for example, the step of lyophilization. After lyophilization only the solvent is removed but impurities remain together with the sodium salt of pravastatin. Apart from the aforementioned, lyophilization is not very economical in large-scale production operations. During precipitation due to nonselectivity of the process, impurities precipitate together with the desired substance. Compared to both aforementioned processes for the preparation of pharmaceutical substances in the solid form, crystallization is the only selective process wherein the molecules of the desired substance are selectively incorporated into the crystal matrix. The possibility of inclusion of impurities into the crystal is minimal because only small size molecules are able to incorporate into the intermolecular space inside a crystal (related impurities, which are usually within the desired substance size range may only be incorporated into this space with great difficulty), incorporation of other molecules into the crystal matrix is not favored thermodynamically.
The advantage of substances in the crystal structures over those in amorphous structures is that their physical as well as chemical parameters are better defined and they are more stable. The latter is of particular importance for the substances which by nature are unstable and sensitive to different ambient influences, such as light, pH, atmosphere and temperature. Pravastatin sodium is particularly sensitive to these negative influences.
It has been known that thus far the sodium salt of pravastatin may only be present in an amorphous form. The Merck Index 1996 describes the sodium salt of pravastatin as an amorphous substance.
Methods for the preparation of the sodium salt of pravastatin described in many patents, for example U.S. Pat. No. 4,537,859, U.S. Pat. No. 4,448,979, U.S. Pat. No. 4,410,629 and U.S. Pat. No. 4,316,227, afford only the preparation of an amorphous form. In the methods disclosed, after separation of the chromatographic columns, the fractions obtained comprising the sodium salt of pravastatin are lyophilized and the sodium salt in a solid amorphous form is obtained.
The WO-A-98/45410 discloses that after the sodium salt of pravastatin is purified using reverse-phase chromatography, alleged crystals may be obtained by precipitation in the ethanol/ethyl acetate mixture; however, the experiments we have carried out suggest that this combination of the solvents affords the preparation of pravastatin in the amorphous form and not in the crystalline form.
It is an object of the present invention to provide the sodium salt of pravastatin in crystalline form which has improved purity and stability compared to the salts described in the prior art mentioned above.
Further, it is another object of the present invention to provide a process for the preparation of such a sodium salt of pravastatin.
These and further objects are accomplished by the present invention.
In a first aspect, the present invention provides the sodium salt of pravastatin in a crystalline form. Furthermore, the present invention also provides the sodium salt of pravastatin in a specific crystalline form, wherein the crystals in an X-ray diffraction measurement produce a signal sufficiently comparable to that illustrated in the diffractogram shown in FIG. 2.
In a second aspect, the present invention provides a process for the preparation of the sodium salt of pravastatin in a crystalline form comprising the steps of: (a) dissolving the sodium salt of pravastatin in a lower aliphatic alcohol; (b) adding ethyl acetate to the alcoholic solution of the sodium salt of pravastatin; (c) cooling of said alcohol/ethyl acetate mixture; and (d) crystallizing the sodium salt of pravastatin.
According to a third aspect of the present invention, there is further provided a pharmaceutical formulation containing the sodium salt of pravastatin in the aforementioned crystalline forms.
The crystalline sodium salt of pravastatin according to the present invention is particularly suitable for the preparation of pharmaceutical products for the treatment of hypercholesterolemia and hyperlipidemia.
The various features of novelty which characterize the invention are pointed out with particularly in the claims annexed to and forming a part of the disclosure. For a better understanding of the invention, its operating advantages, and specific objects attained by its use, reference should be had to the drawing and descriptive matter in which there are illustrated and described preferred embodiments of the invention.